OVERALL PROGRAM SUMMARY/ABSTRACT In this P01 proposal entitled: ?Novel Approaches to Understand the Pathogenesis and Treat Alzheimer?s Disease?, we seek to gain a better understanding of the heterogeneous pathogenesis of AD and how it is influenced by apolipoprotein (apo) E isotypes. The apoE4 allele is the major genetic risk factor for late-onset AD and has been strongly associated with increased amyloid plaques deposition in brain parenchyma and advanced vascular amyloid pathology; as well as, enhanced A? oligomerization. ApoE is also involved in synaptic plasticity, glucose metabolism, mitochondrial function, and vascular integrity. Currently, there is no consensus on how different apoE genotypes contribute to the pathogenesis of AD. The interrelated studies proposed in the three projects of this P01 will help elucidate this complex role of apoE in AD. Hence this P01 is addressing an issue of great significance. We propose an integrated, multidisciplinary research endeavor that brings together investigators with an extensive history of successful collaboration, who have expertise in diverse areas including proteomics, bioinformatics, neuropathology, AD mouse models, immunology, MRI, PET, medicinal chemistry and biomarker studies. Across all projects we will apply our innovative proteomic methods (with the assistance of the proteomics/neuropathology Core B) and use of common AD models and behavioral assessments (with the assistance of the transgenic/behavioral Core C), along with state-of-the-art biomarker technology using SIMOA and P01 investigator developed MRI methodologies, to ensure synergism across all P01 studies. Scientific rigor of the P01 will be ensure by the Biostatistics and Bioinformatics Core (Core D). The three projects of this P01 are focused on the differential role apolipoprotein E (apoE) isoforms play in: 1) AD plaque and vessel amyloid development as assessed by unbiased proteomics across the full spectrum of AD pathology (Project 1); 2) innovative therapeutic approaches that target the A?/apoE interaction (Project 2); and 3) responses to our novel therapeutic immunomodulation that targets abnormal conformation (Project 3). Combined our efforts are anticipated to enhance our understanding of the differential effects of apoE isotypes on AD pathogenesis and accelerate the discovery of effective therapeutic approaches that address these diverse roles.